Abstract：
Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.
摘要：
非小细胞肺癌（NSCLC），一种常见的恶性肿瘤,需要更深入的发病机制研究。自噬是一种进化上保守的溶酶体降解过程，在癌症进展过程中经常被阻断。迫切需要确定NSCLC中新型自噬相关调节因子。这里,我们发现pirin在非小细胞肺癌中上调，其表达与不良预后呈正相关。过表达pirin抑制自噬并促进NSCLC增殖。然后，我们进行了基于数据非依赖性采集的定量蛋白质组学，以鉴定pirin过表达（OE）或pirin敲低（KD）细胞中的差异表达蛋白（DEP）。在受pirin管制的DEP中，鸟氨酸脱羧酶1（ODC1）在pirin-KD细胞中下调，而与pirin过表达一起上调。在A549和H460细胞中,ODC1耗尽逆转了pirin诱导的自噬抑制和促增殖作用。免疫组化显示ODC1在NSCLC癌组织中高表达，与pirin呈正相干。值得注意的是,pirinhigh/ODC1high的NSCLC患者在总生存期方面具有更高的风险。总之,我们将pirin和ODC1鉴定为NSCLC的新型预后生物标志物簇,并强调了pirin/ODC1/自噬轴在该癌症类型中的潜在致癌作用.靶向该途径代表了治疗NSCLC的可能的治疗方法。
